SUMMARY Non-typhoidal Salmonella (NTS) cause a severe inflammatory diarrhea and infect an estimated 100 million patients per year, of which 1.4 million are in the United States. Although the early inflammatory response in the intestinal mucosa is critical to control NTS infection and confine it to the gut, recent studies conducted by our group and others have shown that elements of intestinal inflammation are exploited by NTS to thrive in the inflamed gut and to transmit to nave hosts. Multiple mechanisms - many of which are still unknown - play a role in this process. In this regard, we found that sequestration of essential metal ions, a process known as ?nutritional immunity?, is an arm of the host response that is exploited by NTS to thrive in the inflamed gut and to compete with the intestinal microbiota. The primary objective of this application is to continue to elucidate the mechanisms by which NTS thrive in the inflamed intestinal mucosa, evade the host's nutritional immune response, and compete with the resident microbiota for metal nutrients. Our central hypothesis is that NTS exploits nutritional immunity to outcompete the microbiota for the essential metal micronutrients iron, zinc, and manganese. The inflamed gut is a hostile environment where metal ion deprivation enhances the proliferation of pathogens like NTS that can efficiently acquire metal ions. We reason that understanding how NTS exploits nutritional immunity to its own advantage will lead to new approaches to limit the replication of NTS in the inflamed gut and to impede its transmission to other hosts. The proposed work is innovative because it establishes new concepts on how a pathogen can exploit host mucosal defenses. It is our expectation that the outcome of this study will identify mechanisms by which NTS, and likely other pathogens or pathobionts, exploits nutritional immunity to thrive in the inflamed gut, potentially leading to new therapies and vaccines to target metal ion acquisition by the pathogen.